The present invention relates to compositions having enhanced or improved bioavailability for a novel tricyclic amide compound.
WO 97/23478, published Jul. 3, 1997, discloses tricyclic amides useful for inhibition of G-Protein function and for treatment of proliferative diseases. One particular compound (+)-4-[4-(8-chloro-3,10-dibromo-6,11-dihydro-5H-benzo [5,6cyclohepta[1,2-b]pyridin-11-yl)-1-piperidinyl]-2-oxoethyl]-1-piperidinecarboxamide (Compound I) 
was found to have potent activity for inhibiting the abnormal growth of cells, and for inhibiting farnesyl protein transferase.
WO 97/23478 discloses that examples of suitable compositions of this compound include solid compositions such as tablets and capsules.
In developing a solid dosage form, e.g. a tablet or capsule, it was observed that crystalline Compound I had very poor bioavailability, did not seem suitable for development as a tablet or capsule.
The oral bioavailability of active compounds can vary with the dosage form of the active compound. For example, it is known that solution dosages and suspensions generally give rise to higher bioavailability than capsules or tablets (see Pharmacokinetics Process and Mathematics, ACS Monograph 185, Chapter 5, page 57 (1986), and J. G. Nairn, Remington""s Pharmaceutical Sciences, 18th edition (1990)). However, tablets and capsules are more convenient dosage forms, and it would be preferable to have a tablet or a capsule dosage form of an active compound that has comparable bioavailability as that of solution or suspension.
A formulation of compound I that provides enhanced bioavailability of the compound would be a welcome contribution to the art. A formulation of the above compound that can be manufactured in a tablet or capsule form that has greater bioavailability, or comparable to that of a suspension would also be a welcome contribution to the art. This invention provides these contributions to the art. Thus, this invention overcomes the problem of making active compounds that have a very-low bioavailability into more bioavailable form.
The present invention provides a pharmaceutical composition comprising:
a molecular dispersion, said molecular dispersion comprising a compound having the formula 
molecularly dispersed in a polymer matrix.
This invention also provides solid dosage forms comprising the molecular dispersion described above. Solid dosage forms include tablets, capsules and chewable tablets. Known excipients can be blended with the molecular dispersion to provide the desired dosage form. For example, a capsule can contain the molecular dispersion blended with (a) a disintegrant and a lubricant, or (b) a disintegrant, a lubricant and a surfactant. A tablet can contain the molecular dispersion blended with at least one disintegrant, a lubricant, a surfactant, and a glidant. The chewable tablet can contain the molecular dispersion blended with a bulking agent, a lubricant, and if desired an additional sweetening agent (such as an artificial sweetener), and suitable flavors.
The compound of Formula I is a tricyclic amide compound described in WO 97/23478, published Jul. 3, 1997.
Reference to the xe2x80x9ccompound of Formula Ixe2x80x9d also includes reference to the enantiomers of the compound.
As used herein, the term xe2x80x9cmolecularly dispersedxe2x80x9d or xe2x80x9cmolecular dispersionxe2x80x9d refers to a condition in which: (a) compound (I) is in a substantially amorphous form and is dispersed in a polymer matrix (also known as a xe2x80x9csolid solutionxe2x80x9d), or (b) compound (I) is in crystalline form and is dispersed in a polymer matrix, the crystals being so fine, that they can not be detected by x-ray diffraction analysis.
As used herein, the term xe2x80x9csubstantially amorphousxe2x80x9d refers to a condition in which greater than 90% of compound (I) is in amorphous form.
When the molecular dispersion is a dispersion of compound (I) in substantially amorphous form, such molecular dispersions may be prepared by dissolving the compound and a polymer in a suitable organic solvent, or mixture of organic solvents, and then removing the solvent to produce a molecular dispersion. The molecular dispersions formed in this manner are such that compound (I) is in substantially amorphous form, and homogeneously dispersed in the polymer matrix. Preferably, the polymer is a water soluble polymer. When water insoluble polymers are employed instead of water soluble polymers, the resulting molecular dispersions have enhanced bioavailability, but will exhibit a sustained release profile.
Alternatively, the molecular dispersions may be prepared by dissolving the compound of formula (I) in an organic solvent that will swell a polymer matrix instead of dissolving the polymer. The polymer matrix will absorb the active solution, rendering compound (I) in a fine crystalline or amorphous state dispersed throughout the matrix, upon subsequent evaporation of the solvent.
The preparation of solid solutions from soluble polymers is well known in the artxe2x80x94see, for example, page 173 in Kollidonxe2x80x94polyvinylpyrrolidone for the pharmaceutical industry by BASF. The preparation of solid solutions from insoluble polymeric matrices are also known in the art, and such preparations are similar to those for drug loading into crosslinked hydrogelsxe2x80x94see for example, U.S. Pat. No. 4,624,848 and Lee, P. I., Kinetics of Drug Release from Hydrogel Matrices, Journal of Controlled Release, Vol. II, pages 277 to 288 (1985).
Suitable water soluble polymers for use as the polymer matrix include, but are not limited to: polyvinylpyrrolidone (Povidone); hydroxypropyl methylcellulose, hydroxypropyl-cellulose; polyethylene glycol; polyethylene oxide; gelatin; carbomer; carboxymethyl-cellulose; methyl cellulose; methacrylic acid copolymer; ammonio methacrylate copolymer; hydroxy ethyl cellulose; polyvinyl alcohol; cellulose acetate phthalate; hydroxypropyl methylcellulose phthalate; and polyvinyl alcohol phthalate.
Suitable water insoluble polymers for use as the polymer matrix include, but are not limited to: crospovidone; sodium starch glycolate; and croscarmellose.
Preferably, the polymer used for the polymeric matrix is selected from the group consisting of polyvinylpyrrolidone (Povidone), hydroxypropyl methylcellulose, hydroxypropyl-cellulose, and polyethylene glycol. Polyvinylpyrrolidone is particularly preferred. When a water isoluble polymer is employed, crospovidone is preferred.
All of the foregoing polymers are well known in the art.
Polyvinylpyrrolidone represents polymers of 1-vinyl-2-pyrrolidone. It is available commercially as Povidone or Kollidon having a weight average ranging from about 12,000 to about 150,000. Generally, the polyvinylpyrrolidone used has a weight average in the range of about 7000 to about 54,000, with about 28,000 to about 54,000 being preferred, and about 29,000 to about 44,000 being more preferred.
Crospovidone represents water insoluble synthetic cross-linked homopolymers of N-vinyl-2-pyrrolidone. Generally, the crospovidone has a particle size of about 20 xcexcM to about 250 xcexcM, and preferably about 50 xcexcM to about 250 xcexcM (see, for example, Kollidon, polyvinylpyrrolidone for the pharmaceutical industry, by BASF).
Preferably, the ratio of the compound of formula (I) to polymer is about 1:0.5 to about 1:4, more preferably about 1:1 to about 1:3, and most preferably, about 1:1.
When the molecular dispersions of the present invention are prepared by dissolving the compound of formula I and the polymer in an organic solvent or mixture of organic solvents, suitable organic solvents include, but are not limited to methylene chloride, methanol, ethanol, isopropanol, tetrahydrofuran, or mixtures thereof.
The solvent may be removed by conventional means: e.g., evaporating the solvent under a hood; use of a double drum dryer, or spray dryer or supercritical fluid extraction process.
The composition comprising the molecular dispersion can, optionally, further comprise excipients selected from the group consisting of: disintegrants, lubricants, surfactants, glidants, artificial sweeteners, bulking agents, colorants and one or more flavorants.
Generally the compound I ranges from 15 to 60% in the formulations (tablets, capsules, or powders).
Generally, the composition comprising the molecular dispersion can, optionally, further comprise: about 5 to about 40 wt % of one or more disintegrants, about 0.1 to about 1 wt % of one or more lubricants, about 3 to about 15 wt % of one or more surfactants, about 0.1 to about 5 wt % of one or more glidants, about 0.1 to about 1 wt % of one or more artificial sweeteners, about 25 to about 75 wt % of one or more bulking agents, about 0.1 to about 1 wt % of one or more colorants (coloring agents), and/or about 0.1 to about 1 wt % of one or more flavorants (flavoring agents).
Suitable disintegrants are selected from the group consisting of: croscarmellose sodium (a cross linked polymer of carboxymethylcellulose sodium, see NF XVII page 1922 (1990)), crospovidone, starch NF; polacrilin sodium or potassium and sodium starch glycolate. Preferably, the disintegrants are selected from croscarmellose sodium or crospovidone. Preferably, croscarmellose sodium is used as the disintegrant in compositions for capsules. Preferably, crospovidone is used as the disintegrant in compressible tablets. Those skilled in the art will appreciate that it is desirable for compressible tablets to disintegrate within 30 minutes; therefore, the disintegrant used preferably results in the disintegration of the tablet within 30 minutes. It has been found that disintegrants, such as croscarmellose sodium and crospovidone, used in amounts of less than 30 wt % did not produce tablets which disintegrated within 30 minutes. It is believed that significantly higher amounts of such disintegrants would result in a tablet that disintegrates within 30 minutes.
Suitable lubricants include talc, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oils and the like. Preferably, magnesium stearate is used.
Suitable surfactants include block copolymers of ethylene oxide and propylene oxide such as Pluronic(copyright) F-68 (Poloxamer 188), Pluronic(copyright) F87 (Poloxamer 237), Pluronic(copyright) F108 (Poloxamer 338), Pluronic(copyright) F127 (Poloxamer 407) and the like. Preferably, Pluronic(copyright) F-68 is used. According to BASF Corporation""s Technical Bulletin (1995), Pluronic(copyright) is a registered tradename for block copolymers of ethylene oxide and propylene oxide represented by the chemical structure HO(C2H4O)a(C3H6O)b(C2H4O)aH wherein for: (a) Pluronic(copyright) F-68, a is 80 and b is 27; (b) Pluronic(copyright) F87, a is 64 and b is 37; (c) Pluronic(copyright) F108, a is 141 and b is 44; and Pluronic(copyright) F127, a is 101 and b is 56. The average molecular weights of these block copolymers are 8,400, 7,700, 14,600 and 12,600 for Pluronic F-68, Pluronic F-87, Pluronic F108 and Pluronic F127, respectively.
Suitable glidants include silicon dioxide, talc and the like. Preferably, silicon dioxide is used.
Suitable bulking agents include xylitol, mannitol, compressible sugars, lactose, and microcrystalline celluloses. Preferably, xylitol is used for chewable tablets.
Suitable artificial sweeteners include saccharin, cyclamates and aspartame.
If desired, known flavorants and known FD and C colorants can be added to the composition.
The composition comprising the molecular dispersion can be produced in solid dosage forms. Solid dosage forms include capsules (e.g., soft gelatin capsules and hard gelatin capsules) tablets (including, for example, coated tablets, gel coated tablets and enteric coated tablets), and chewable tablets. These dosage forms can be produced by methods well known in the artxe2x80x94see for example Lachman et al., The Theory and Practice of Industrial Pharmacy, 2nd Edition, Lea and Febiger, Philadelphia, pages 321-344 and pages 389-404 (1976).
For capsule dosage forms, the composition comprising the molecular dispersion generally further comprises disintegrants, lubricants, and, optionally, surfactants. Thus, a composition for use in capsules can comprise about 65 to about 90 wt % of the molecular dispersion, about 5 to about 20 wt % of one or more disintegrants, about 0.2 to about 1 wt % of one or more lubricants, about 1-3% of glidant and, optionally, about 3 to about 15 wt % of one or more surfactants.
For example, a composition for use in a capsule dosage form comprises: about 80 to about 85 wt % of the molecular dispersion, about 5 to about 10 wt % of one or more disintegrants, about 0.5 to about 1 wt % of one or more lubricants, about 0.5 to about 1.5% glident and about 3 to 10% of surfactant.
Another example of a composition for use in a capsule dosage form is a composition comprising about 70 to about 85 wt % of the molecular dispersion, about 5 to about 20 wt % of one or more disintegrants, about 0.3 to about 1 wt % of one or more lubricants, and about 5 to about 15 wt % of one or more surfactants and 1-3% glidant. In general, the compositions for capsule dosage forms contain the molecular dispersion, one disintegrant, one lubricant, one glident and optionally, one surfactant. Preferably, the disintegrant in the capsule compositions is croscarmellose sodium.
For a compressible tablet dosage form, the composition comprising the molecular dispersion generally further comprises disintegrants, lubricants, surfactants, and glidants. Thus, a composition for use in compressible tablets can comprise about 50 to about 75 wt % of the molecular dispersion, about 20 to about 45 wt % of one or more disintegrants, with about 28 to about 35 wt % of one or more disintegrants being preferred, about 0.2 to about 1 wt % of one or more lubricants, about 4 to about 10 wt % of one or more surfactants, and about 0.2 to about 0.6 wt % of one or more glidants. Preferably, the disintegrant is crospovidone. More preferably, the disintegrant is crospovidone in an amount of about 8 to about 40 wt %. Most preferably, the disintegrant is crospovidone in an amount of about 25 to about 35 wt % and another disintegrant (preferably croscarmellose sodium) is used in amounts of about 8 to about 25 wt %.
When used as a disintegrant, the crospovidone generally has a particle size of about 20 xcexcM to about 250 xcexcM, with about 50 xcexcM to about 250 xcexcM being preferred.
In addition to the disintegrant, the compressible tablet also preferably comprises one lubricant, one surfactant and one glidant.
For chewable tablets, the composition generally comprises about 20 to about 50 wt % of the molecular dispersion, about 78 to about 98 wt % of a bulking agent (e.g., a sugar such as xylitol), and about 0.2 to about 1 wt % of a lubricant, optionally about 0.2 to about 1 wt % of an artificial sweetener (e.g., sodium saccharin or aspartame), and optionally about 0.2 to about 1 wt % of a colorant.
A preferred composition for tablets comprises: (1) about 58.8 wt % of a molecular dispersion comprising (a) a compound of Formula I and (b) povidone, wherein the ratio of said compound to said polymer is about 1:1; (2) about 32.6 wt % of croscarmellose sodium (disintegrant); (3) or about 32.6 wt % of crospovidine (disintegrant); (4) about 0.3 wt % of magnesium stearate (lubricant); (5) about 7.4 wt % of Pluronic(copyright) F-68 (surfactant); and about 0.9 wt % of silicon dioxide (glidant). More preferably, the povidone has a molecular weight of about 29,000 to about 44,000. A preferred composition is illustrated in Examples below.
The formulation to be tested was administered orally to male cynomolgus monkeys in a single dose (PO, single). The number of monkeys for each test is indicated by the letter xe2x80x9cNxe2x80x9d followed by an equal sign and a number. Thus, xe2x80x9c(N=6)xe2x80x9d means the formulation was administered to six monkeys. The total amount of the compound of Formula I administered was 100 or 200 mg given as one capsule or tablet containing 100 or 200 mg each. The administered dose (tablet, capsule or control suspension) was slowly washed down with 10 mL of water. Blood samples were taken at 15, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, and 48 hours in heparinized syringes. Plasma for analysis was obtained by centrifugation at 4xc2x0 C. Plasma samples (one per time point) were split and stored at xe2x88x9220xc2x0 C. until assayed as described below.
The monkeys to be tested were fed two biscuits in the morning on the day of drug administration.
Monkeys that were fasted were not given any food overnight before drug administration and were fed normally after the 4-hour time point after drug administration.
Samples of monkey plasma were collected at selected time intervals. The plasma was analyzed by a high pressure liquid chromatograph (HPLC) procedure with ultraviolet detection. AUC (area under the plasma concentration-time curve, 0-72 hours) values were calculated using standard procedures to determine the relative bioavailability of the compound in the tested formulations. The larger the AUC value, the greater the bioavailability.
A suspension of the compound of Formula I was used as a control. The control was made by suspending sufficient compound of Formula I in methyl cellulose solution to provide a dose of 30 mg/kg of body weight of monkey. The 0.4% methyl cellulose solution was made by adding 4 grams of methyl cellulose to one liter of distilled water and heating at about 80xc2x0 C. with stirring for about 1xc2xd hours.
The results of the bioavailability assay are given in terms of percent-relative bioavailability (AUC ratio) compared to amorphous suspension of Compound I in 0.4 methyl cellulose solution.